Alzheimer's disease (AD) is a devastating neurodegenerative disease that affects more than 35 million people (including 5 million Americans) worldwide, and this number is expected to reach more than 115 million by the year 2050. Recent disappointing clinical trials of bapineuzumab and solanezumab in AD treatment further aggravate the problem. There is currently no definitive biomarker for early diagnosis or therapy of AD. The field is calling for transformative technologies and approaches. In response to PA-11-335, Newomics Inc. proposes to develop integrated silicon microfluidic chips, termed AD-MS chips, as a revolutionary platform for rapid, sensitive, and specific biofluids-based early diagnosis of AD. The core technology will be based on Newomics' breakthrough silicon-microfluidic-chip, the multinozzle emitter array chip (MEA chip-2012 R&D100 award), which enables liquid chromatography-nanoelectrospray ionization mass spectrometry (LC-nanoESI/MS)-based, highly sensitive, highly specific, high-throughput, and multiplex measurements of multiclass analytes (peptides, proteins, and metabolites) at the Omics level, from small volumes of samples. The project is also based on our recent discovery of several proteoforms in human plasma as potential AD biomarkers through top-down proteomics studies using our MEA chips. In this SBIR project, we will develop AD-MS chips as a high-throughput and multiplex multi-omics platform. AD-MS chips will enable high-throughput and multiplex measurements of multiclass analytes (peptides, proteins, and metabolites), from small volumes of human plasma and cerebrospinal fluid (CSF) samples, thereby dramatically accelerating the discovery, validation, and clinical application of Multiclass Biomarker Panel (MBP) for AD diagnosis. If validated in future prospective clinical studies, AD-MS chips will enable rapid, sensitive, and affordable biofluids-based early diagnosis of AD.